The present invention relates to stable and non-hygroscopic double salts of fumaric acid (hereinbelow xe2x80x9cdouble fumaratesxe2x80x9d) with a xe2x80x9ccarnitinexe2x80x9d, wherein by xe2x80x9ccarnitinexe2x80x9d either L-carnitine or isovaleryl L-carnitine are meant and an amino acid. The invention also relates to food supplements, dietary supplements, nutraceuticals and drugs containing said double fumarates.
Fumaric acid [(E)-2-butenedioic acid] exhibits interesting applications in both the nutritional and therapeutical field.
It is used as substitute for both tartaric acid which may bring about unpleasant gastrointestinal side effects due to its laxative effects, in the preparation of beverages and baking powders, and citric acid in fruit drinks.
The cardioprotective effect of fumaric acid has been assessed in the perfused rat heart (La Plante et al. xe2x80x9cEffects and metabolism of fumarate in the perfused rat heart. A 13C mass isotopomer studyxe2x80x9d, Am. J. Physiol. 272: E74-E82, 1997) and in the immature myocardium (Pearl et al. xe2x80x9cFumarate enriched blood cardioplegia results in complete functional recovery of immature myocardiumxe2x80x9d Ann. Thorac. Surg. 57: 1636-41, 1993).
Furthermore, fumaric acid is a xe2x80x9cpharmacologically acceptable acidxe2x80x9d: its salts are in fact encompassed in the list of xe2x80x9cFDA-approved commercially marketed saltsxe2x80x9d published e.g. in the Journal of Pharmaceutical Sciences, Vol. 66, No. 1, (1977) pages 1-19.
Conversion of drugs to their respective pharmacologically acceptable salt forms is a widely utilized means for optimizing the administration forms or certain properties of the drugs, such as stability, hygroscopicity, flowability and the like.
Both L-carnitine acid fumarate and isovaleryl acid fumarate are known compounds. (Fumaric acid is a dicarboxylic acid: in the aforesaid acid fumarates only one of the two carboxylic groups is salified).
L-carnitine acid fumarate, whose preparation and physico-chemical properties are disclosed e.g. in U.S. Pat. No. 4,602,039, has been developed in order to overcome the complex problems of storage and processing due to L-carnitine inner salt hygroscopicity. L-carnitine acid fumarate is in fact very stable and, without provoking gastrointestinal side effects, shows a profile of humidity resistance even better than that of L-carnitine tartrate, a further non-hygroscopic salt which was also developed to overcome L-carnitine hygroscopicity.
The tartrate, however, has the advantage that both its carboxylic groups are salified with L-carnitine and consequently it contains a higher percentage in L-carnitine (68% vs. 58%).
Also isovaleryl L-carnitine acid fumarate, whose preparation is disclosed in the U.S. Pat. No. 5,227,518, is a stable compound endowed with considerable resistance to humidity.
Every endeavour made to salify also the free carboxylic group of acid fumarates wherein the other carboxylic group is salified with L-carnitine or isovaleryl L-carnitine has failed to-date. For instance, the attempt of preparing L-carnitine fumarate (i.e. the neutral salt which would have the advantage of a very high percentage in L-carnitine, about 73.5% vs. 68% in the tartrate and 58% in the acid fumarate) results in a highly hygroscopic substance which likely consists of a mixture of L-carnitine acid fumarate and L-carnitine inner salt. It is this latter which imparts high hygroscopicity to the end product as a whole.
Similar failures occur if the attempt is made to salify the free carboxylic group of acid fumarates with alkanoyl L-carnitines, such as acetyl and propionyl L-carnitines.
It is an object of the present invention to provide stable, non-hygroscopic double fumarates wherein one of the carboxylic groups of fumaric acid is salified with either L-carnitine or isovaleryl L-carnitine and the other carboxylic group is also salified with a compound endowed with useful nutritional, dietary or therapeutical properties.
It is, therefore, apparent that the utility of the salts of the present invention is to be found not only in their lack of hygroscopicity and high stability, but also insofar as both their cationic moieties contribute to the nutritional, energetic and/or therapeutic efficacy of the salt as a whole. The aforesaid efficacy of these novel salt is, therefore, not to be attributed exclusively to the xe2x80x9ccarnitinexe2x80x9d moiety of the salt.
The aforesaid object is achieved by the double fumarates of L-carnitine or isovaleryl L-carnitine and an amino acid having the formula (I): 
wherein: R is hydrogen or isovaleryl; and
[A+] is a positively charged amino acid selected from the group consisting of creatine, ornithine, lysine, arginine and hystidine.
The following compounds of formula (I) are to be considered specifically encompassed by the present invention:
L-carnitine and creatine fumarate;
isovaleryl L-carnitine and creatine fumarate;
L-carnitine and ornithine fumarate;
isovaleryl L-carnitine and ornithine fumarate;
L-carnitine and lysine fumarate;
isovaleryl L-carnitine and lysine fumarate;
L-carnitine and arginine fumarate;
isovaleryl L-carnitine and arginine fumarate;
L-carnitine and hystidine fumarate; and
isovaleryl L-carnitine and hystidine fumarate.
Lysine, arginine and hystidine are amino acids occurring in proteins, i.e. they are three out of the twenty amino acids which are obtained via controlled hydrolysis of naturally occurring proteins (see, e.g., J. David Rawn, Biochemistry, Chapter 3 xe2x80x9cAmino acids and the primary structure of proteinsxe2x80x9d; McGraw-Hill, 1990).
Whilst in order to illustrate the nutritional and therapeutic efficacy of the amino acids in general reference is made to the conspicuously vast literature published to-date on this matter (see, e.g., F. Fidanza and G. Liguori, Nutrizione umana, Chapter 3: xe2x80x9cLe proteinexe2x80x9d, Casa Editrice Libraria Idelson, 1995; and I. Goldberg (Ed.), Functional Foods, Chapter 12, xe2x80x9cAmino acids, peptides and proteinsxe2x80x9d Chapman and Hall, Inc. 1994), it is deemed useful to briefly address the topic of creatine and ornithine in view of their peculiar physiological role.
Creatine is an amino acid present in considerable amounts in the skeletal muscle tissue of vertebrates wherein about ⅔ thereof occurs as creatine phosphate.
Creatine is biosynthesized mainly in the liver and kidneys from three amino acids: glycine which provides the carbon skeleton, arginine which releases the amidino group and methionine which releases the methyl group. Creatine is excreted with urine as creatinine. Creatine can be taken with the diet since it is principally present in meat. However, in order to take 10 grams/day of creatine, 2.5 kg of meat should be eaten. The exogenous supply and endogenous biosynthesis must compensate for the daily turn-over of creatine to creatinine which in a 70-kg male subject can be estimated at about two grams.
The physiologic role of creatine is extremely important: principally in the skeletal muscle, but in the brain, liver and kidneys as well, creatinexe2x80x94by reversibly taking up ATP""s phosphate groupsxe2x80x94plays the role of reservoir of the energy-rich phosphate radicals. This reaction is critically important since ATP can not be stored in tissues in excess of a very limited threshold. It is creatine phosphate whose content in tissues is five times as much that of ATP, which provides for phosphate groups supply. Following a moderately wearying physical exertion, the creatine phosphate present in the skeletal muscle decreases in a far relevant amount than ATP does, thus showing that creatine phosphate rephosphorilates ADP as ATP becomes dephospharilated.
When the rate of ATP""s metabolic production exceeds ATP""s utilization, this results in creatine phosphate formation. Creatine phosphate is, therefore, a reservoir of immediately available energy, suitable for counterbalancing energy demands exceeding ATP""s synthesis rate in metabolic phosphorylation processes.
Creatine is mainly taken by athletes and sportsman insofar as it increases the skeletal musculature if its intake is accompanied by lasting physical exertion. Creatine intake results in a lowering of fat while it enhances skeletal muscle. Recent researches have shown that the combined intake of creatine and carbohydrates enhances creatine effects owing to insuline production that is stimulated by simple sugars which likely play a role in creatine exportation to muscle cells.
Ornithine, a non-proteogenic amino acid, is a lower homolog of lysine and an important intermediate in urea biosynthesis cycle wherein it is synthesized by arginine transguanidinization. Ornithine can also be converted to glutamic acid.
The fumarates of formula (I) fully accomplish the object of the present invention insofar as they are not only stable, non-hygroscopic compounds which favourably lend themselves to the preparation of solid presentation forms which are the preferred ones for nutraceuticals and nutritional and dietary supplements, but also combine in single salts the complementary physiological activities of a xe2x80x9ccarnitinexe2x80x9d and of the aforesaid amino acids.
For instance, those fumarates which combine creatine and a xe2x80x9ccarnitinexe2x80x9d synergistically in a single compound, stimulate on one hand the production of energy in the myocytes, particularly in type I muscle fibers, allowing important energy-carriers (the fatty acids) to enter the mitochondrion, and, on the other hand, stimulate the ATP formed via cellular respiration (oxidative phosphorilation) to leave the same organelle. The ATP provides the mechanical energy needed for muscle contraction.
The following non-limiting examples illustrate the preparation and physico-chemical properties of some compounds of the present invention.